Circular RNA AGAP1 Stimulates Immune Escape and Distant Metastasis in Renal Cell Carcinoma.

ABSTRACT

Clear cell renal cell carcinoma (ccRCC) is the most representative subtype of renal cancer, with a highly aggressive phenotype and extremely poor prognosis. Immune escape is one of the main reasons for ccRCC growth and metastasis, in which circular RNAs (circRNAs) play critical roles. Therefore, this research studied circAGAP1-associated mechanisms in immune escape and distant metastasis in ccRCC. circAGAP1/miR-216a-3p/MKNK2 was overexpressed or down-regulated by cell transfection. EdU assay, colony formation assay, scratch assay, Transwell assay, immunoblotting, and flow cytometry were used to evaluate cell proliferation, migration, invasion, EMT, and immune escape, respectively. Dual-luciferase reporting assay and RIP assay were used to evaluate the targeting relationship between circAGAP1/miR-216a-3p/MKNK2. Xenotransplantation in nude mice was used to evaluate the growth of ccRCC tumors in vivo. Here, circAGAP1 high expression was positively correlated with higher histological grade and distant metastasis and was a prognostic indicator for ccRCC. Depleting circAGAP1 effectively hampered the proliferative, invasive, and migratory capacities, EMT, and immune escape of ccRCC cells. Correspondingly, silencing circAGAP1 delayed tumor growth, distant metastasis, and immune escape in vivo. Mechanistically, circAGAP1 sponged the tumor suppressor miR-216a-3p, thereby preventing miR-216a-3p from inhibiting MAPK2. Collectively, our findings demonstrate that circAGAP1 exerts a tumor suppressor function through miR-216a-3p/MKNK2 during the immune escape and distant metastasis in ccRCC, and suggest that circAGAP1 may be a novel prognostic marker and therapeutic target for ccRCC.